Janssen Research & Development, Johnson & Johnson, 145 King of Prussia Road, Radnor, Pennsylvania 19087, United States.
Mol Pharm. 2012 May 7;9(5):1100-8. doi: 10.1021/mp200352q. Epub 2012 Apr 13.
Poorly water-soluble weakly basic compounds which are solubilized in gastric fluid are likely to precipitate after the solution empties from the stomach into the small intestine, leading to a low oral bioavailability. In this study, we reported an approach of combining solubilization agents and precipitation inhibitors to produce a supersaturated drug concentration and to prolong such a drug concentration for an extended period of time for an optimal absorption, thereby improving oral bioavailability of poorly water-soluble drugs. A weakly basic compound from Johnson and Johnson Pharmaceutical Research and Development was used as a model compound. A parallel microscreening precipitation method using 96-well plates and a TECAN robot was used to assess the precipitation of the tested compound in the simulated gastric fluid (SGF) and the simulated intestinal fluid (SIF), respectively, for lead solubilizing agents and precipitation inhibitors. The precipitation screening results showed vitamin E TPGS was an effective solubilizing agent and Pluronic F127 was a potent precipitation inhibitor for the tested compound. Interestingly, the combination of Pluronic F127 with vitamin E TPGS resulted in a synergistic effect in prolonging compound concentration upon dilution in SIF. In addition, HPMC E5 and Eudragit L100-55 were found to be effective precipitation inhibitors for the tested compounds in SGF. Furthermore, optimization DOE study results suggested a formulation sweet spot comprising HPMC, Eudragit L 100-55, vitamin E TPGS, and Pluronic F127. The lead formulation maintained the tested compound concentration at 300 μg/mL upon dilution in SIF, and more than 70% of the compound remained solubilized compared with the compound alone at <1 μg/mL of its concentration. Dosing of the solid dosage form predissolved in SGF in dogs resulted in 52% of oral bioavailability compared to 26% for the suspension control, a statistically significant increase (p = 0.002). The enhanced oral bioavailability of the tested compound could be attributed to generation and prolongation of a supersaturated drug concentration in vivo by the solubilizing agents and precipitation inhibitors. The study demonstrates that the combination approach of solubilization agents and precipitation inhibitors provides improved oral bioavailability for a poorly water-soluble weakly basic compound.
水溶性差的弱碱性化合物在胃中被溶解后，当溶液从胃排空到小肠时，可能会沉淀，导致口服生物利用度低。在这项研究中，我们报告了一种结合增溶剂和沉淀抑制剂的方法，以产生过饱和药物浓度，并延长这种药物浓度的时间，以达到最佳吸收，从而提高水溶性差的药物的口服生物利用度。强生制药研发的一种弱碱性化合物被用作模型化合物。使用 96 孔板的平行微筛选沉淀法和 TECAN 机器人分别评估了在模拟胃液 (SGF) 和模拟肠液 (SIF) 中测试化合物的沉淀，以筛选出 lead 增溶剂和沉淀抑制剂。沉淀筛选结果表明，TPGS 维生素 E 是测试化合物的有效增溶剂，Pluronic F127 是测试化合物的有效沉淀抑制剂。有趣的是，Pluronic F127 与 TPGS 维生素 E 联合使用可在 SIF 稀释时协同延长化合物浓度。此外，HPMC E5 和 Eudragit L100-55 被发现是 SGF 中测试化合物的有效沉淀抑制剂。此外，优化 DOE 研究结果表明，包含 HPMC、Eudragit L100-55、TPGS 维生素 E 和 Pluronic F127 的配方是一个理想的配方。该主导配方在 SIF 中稀释时可将测试化合物的浓度保持在 300μg/ml，与低于其 1μg/ml 浓度的化合物相比，超过 70%的化合物保持溶解状态。在狗体内以 SGF 预溶解的固体剂型给药，与混悬剂对照相比，口服生物利用度提高了 52%，这是一个统计学上显著的增加（p=0.002）。测试化合物口服生物利用度的提高可归因于增溶剂和沉淀抑制剂在体内产生和延长过饱和药物浓度。该研究表明，增溶剂和沉淀抑制剂的联合方法为水溶性差的弱碱性化合物提供了提高的口服生物利用度。
